Phase I Study and Cell-Free DNA Analysis of T-DM1 and Metronomic Temozolomide for Secondary Prevention of HER2-Positive Breast Cancer Brain Metastases.

PURPOSE: Preclinical data showed that prophylactic, low-dose temozolomide (TMZ) significantly prevented breast cancer brain metastasis. We present results of a phase I trial combining T-DM1 with TMZ for the prevention of additional brain metastases after previous occurrence and local treatment in patients with HER2+ breast cancer. PATIENTS AND METHODS: Eligible patients had HER2+ breast cancer with brain metastases and were within 12 weeks of whole brain radiation therapy (WBRT), stereotactic radiosurgery, and/or surgery. Standard doses of T-DM1 were administered intravenously every 21 days (3.6 mg/kg) and TMZ was given orally daily in a 3+3 phase I dose escalation design at 30, 40, or 50 mg/m2, continuously. DLT period was one 21-day cycle. Primary endpoint was safety and recommended phase II dose. Symptom questionnaires, brain MRI, and systemic CT scans were performed every 6 weeks. Cell-free DNA sequencing was performed on patients' plasma and CSF. RESULTS: Twelve women enrolled, nine (75%) with prior SRS therapy and three (25%) with prior WBRT. Grade 3 or 4 AEs included thrombocytopenia (1/12), neutropenia (1/12), lymphopenia (6/12), and decreased CD4 (6/12), requiring pentamidine for Pneumocystis jirovecii pneumonia prophylaxis. No DLT was observed. Four patients on the highest TMZ dose underwent dose reductions. At trial entry, 6 of 12 patients had tumor mutations in CSF, indicating ongoing metastatic colonization despite a clear MRI. Median follow-up on study was 9.6 m (2.8-33.9); only 2 patients developed new parenchymal brain metastases. Tumor mutations varied with patient outcome. CONCLUSIONS: Metronomic TMZ in combination with standard dose T-DM1 shows low-grade toxicity and potential activity in secondary prevention of HER2+ brain metastases.

Recurrence Score Testing Does not Appear to Benefit Patients With Grade 1, Progesterone Receptor-Positive Breast Cancers: An Opportunity to Eliminate Overtreatment and Decrease Testing Costs.

BACKGROUND: We previously described a risk prediction model (Anne Arundel Medical Center [AAMC] model) based on pathology which may eliminate the need for recurrence score (RS) testing in select early-stage breast cancers. There is a concern that patients in discordant risk prediction groups (AAMC vs. RS) may be overtreated or undertreated if RS testing were omitted. METHODS: We queried the Surveillance, Epidemiology, and End Results (SEER) database for all breast cancer patients between 2004 and 2015. AAMC low-risk was defined as Grade 1 and progesterone receptor-positive (PR + ) tumors, while AAMC high-risk was defined as Grade 3 or estrogen-negative tumors. RS low-risk group was defined as RS < 16 and age ≤ 50 years, or RS ≤ 25 and age > 50 years. RS high-risk group was defined as RS > 25. RESULTS: A total of 71,212 cases were analyzed. Of these, 590 were AAMC low-risk/RS high-risk discordant, while 5,596 were AAMC high-risk/RS low-risk discordant. For AAMC low-risk/RS high-risk discordant, 10-year breast cancer-specific survival (BCSS) did not differ for patients who received adjuvant chemotherapy versus those who did not (93% chemotherapy vs. 99% unknown/no chemotherapy, p = .12). Overall survival (OS) was also comparable (92% chemotherapy vs. 91% unknown/no chemotherapy, p = .42). In the AAMC high-risk/RS low-risk discordant group, 10-year BCSS (92% chemotherapy vs. 96% unknown/no chemotherapy, p = .06) and OS (87% chemotherapy vs. 90% unknown/no chemotherapy, p = .52) did not differ between adjuvant chemotherapy and unknown/no chemotherapy groups. CONCLUSIONS: Adjuvant chemotherapy in the AAMC low-risk/RS high-risk and AAMC high-risk/RS low-risk discordant groups did not improve survival. This supports consideration of omission of RS testing in Grade 1, PR + tumors. Patients with Grade 3 tumors do benefit from RS testing.

The Impact of Genomic Profiling on Adjuvant Therapy Recommendation in Postmenopausal Women with ER-Positive, T1-2 Breast Cancer: Can Genomic Profiling Eliminate the Need for Sentinel Lymph Node Biopsy?

INTRODUCTION: With the advent of genomic assays, sentinel lymph node biopsy (SLNB) may be less impactful in determining adjuvant breast cancer therapy. We evaluated the influence of SLNB on adjuvant therapy recommendation when the Oncotype DX recurrence score (RS) is known. METHODS: We reviewed postmenopausal women with ER-positive/HER2-negative, pT1-2 breast cancers with non-suspicious axillary ultrasound treated with SLNB at the time of cancer resection, from 2011 to 2015. For each case, the recommended adjuvant therapy based on the actual SLNB was compared with recommendations if SLNB had been omitted (presumed negative). RESULTS: Surgical nodal status was N0 in 184 patients (84.8%), Nmi-N1 in 29 patients (13.4%), and N2-3 in 4 patients (1.8%). SLNB resulted in a recommendation for axillary lymph node dissection in 4.1% (n = 9). Axillary surgery resulted in a change in radiation recommendation (nodal radiation considered or recommended) in 15.2% (n = 33). Of the 147 patients with known RS, 95 patients had RS > 18, 29 had RS 18-25, and 23 had RS < 25. When chemotherapy was only recommended for RS > 25, or N2-3 disease, SLNB changed the recommendation to have chemotherapy in one patient (0.7%), and the recommendation of which chemotherapy regimen (second- vs. third-generation) in an additional 5 patients. CONCLUSION: SLNB changed the recommendation for/against chemotherapy, or the chemotherapy regiment recommended, in 4.8% of postmenopausal women with early-stage, ER-positive/HER2-negative breast cancer, and sonographically negative axilla when using RS > 25 or N2-3 disease as an indication for chemotherapy. Preoperative genomic profiling can guide de-escalation of axillary surgery.

CD25 blockade depletes and selectively reprograms regulatory T cells in concert with immunotherapy in cancer patients.

Regulatory T cells (T(regs)) are key mediators of immune tolerance and feature prominently in cancer. Depletion of CD25(+) FoxP3(+) T(regs) in vivo may promote T cell cancer immunosurveillance, but no strategy to do so in humans while preserving immunity and preventing autoimmunity has been validated. We evaluated the Food and Drug Administration-approved CD25-blocking monoclonal antibody daclizumab with regard to human T(reg) survival and function. In vitro, daclizumab did not mediate antibody-dependent or complement-mediated cytotoxicity but rather resulted in the down-regulation of FoxP3 selectively among CD25(high) CD45RA(neg) T(regs). Moreover, daclizumab-treated CD45RA(neg) T(regs) lost suppressive function and regained the ability to produce interferon-γ, consistent with reprogramming. To understand the impact of daclizumab on T(regs) in vivo, we performed a clinical trial of daclizumab in combination with an experimental cancer vaccine in patients with metastatic breast cancer. Daclizumab administration led to a marked and prolonged decrease in T(regs) in patients. Robust CD8 and CD4 T cell priming and boosting to all vaccine antigens were observed in the absence of autoimmunity. We conclude that CD25 blockade depletes and selectively reprograms T(regs) in concert with active immune therapy in cancer patients. These results suggest a mechanism to target cancer-associated T(regs) while avoiding autoimmunity.

Low-dose cyclophosphamide associated with hemorrhagic cystitis in a breast cancer patient.

Hemorrhagic cystitis is a known complication of high-dose cyclophosphamide treatment, generally occurring at doses greater than 100 g. There are few reports of hemorrhagic cystitis occurring with low-dose cyclophosphamide therapy, and this complication has not been described in breast cancer patients. We present a case of a patient with stage IIB breast cancer who developed clinical, radiographic, and pathologic evidence of hemorrhagic cystitis after a single 600 mg/m(2) dose of cyclophosphamide. Three subsequent cycles of cyclophosphamide with the addition of IV hydration and MESNA were given without complication, and the patient's urologic symptoms resolved. Repeat cystoscopy demonstrated pathologic resolution of the cystitis. We review the literature regarding proposed mechanisms of hemorrhagic cystitis, and discuss the applicability of these hypotheses in our patient.

Intensive care nurses' knowledge of pressure ulcers: development of an assessment tool and effect of an educational program.

BACKGROUND: Critically ill patients are at high risk for pressure ulcers. Successful prevention of pressure ulcers requires that caregivers have adequate knowledge of this complication. OBJECTIVE: To assess intensive care nurses' knowledge of pressure ulcers and the impact of an educational program on knowledge levels. METHODS: A knowledge assessment test was developed. A cohort of registered nurses in a tertiary referral hospital in New Zealand had knowledge assessed 3 times: before an educational program, within 2 weeks after the program, and 20 weeks later. Multivariate analysis was performed to determine if attributes such as length of time since qualifying or level of intensive care unit experience were associated with test scores. The content and results of the assessment test were evaluated. RESULTS: Completion of the educational program resulted in improved levels of knowledge. Mean scores on the assessment test were 84% at baseline and 89% following the educational program. The mean baseline score did not differ significantly from the mean 20-week follow-up score of 85%. No association was detected between demographic data and test scores. Content validity and standard setting were verified by using a variety of methods. CONCLUSION: Levels of knowledge to prevent and manage pressure ulcers were good initially and improved with an educational program, but soon returned to baseline.